Research Article Cite This: ACS Comb. Sci. XXXX, XXX, XXX−XXX
pubs.acs.org/acscombsci
On-DNA Decarboxylative Arylation: Merging Photoredox with Nickel Catalysis in Water Dominik K. Kölmel,*,† Jiang Meng,‡ Mei-Hsuan Tsai,‡ Jiamin Que,‡ Richard P. Loach,† Thomas Knauber,† Jinqiao Wan,‡ and Mark E. Flanagan*,† †
Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States HitGen Inc, Building 6, No. 8, Huigu first East Road, Tianfu International Bio-Town, Shuangliu District, Chengdu City, Sichuan Province, P. R. China
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S Supporting Information *
ABSTRACT: A new catalytic manifold that merges photoredox with nickel catalysis in aqueous solution is presented. Specifically, the combination of a highly active, yet air-stable, nickel precatalyst with a new electron-deficient pyridyl carboxamidine ligand was key to the development of a water-compatible nickel catalysis platform, which is a crucial requirement for the preparation of DNA-encoded libraries (DELs). Together with an iridium-based photocatalyst and a powerful light source, this dual catalysis approach enabled the efficient decarboxylative arylation of α-amino acids with DNA-tagged aryl halides. This C(sp2)−C(sp3) coupling tolerates a wide variety of functional groups on both the amino acid and the aryl halide substrates. Due to the mild and DNA-compatible reaction conditions, the presented transformation holds great potential for the construction of DELs. This was further evidenced by showing that well plate-compatible LED arrays can serve as competent light sources to facilitate parallel synthesis. Lastly, we demonstrate that this procedure can serve as a blueprint toward the adaptation of other established nickel metallaphotoredox transformations to the idiosyncratic requirements of a DEL. KEYWORDS: amino acids, decarboxylative coupling, DNA, nickel catalysis, photoredox catalysis
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INTRODUCTION The merger of transition metal and photoredox catalysis, commonly termed dual catalysis or metallaphotoredox catalysis, has recently led to a cornucopia of novel transformations that typically enable the rapid construction of valuable organic molecules from relatively simple and readily available starting materials.1−3 Among other transition metals, such as chromium,4 cobalt,5 copper,6−8 zinc,9 ruthenium,10 rhodium,11 palladium,12 and gold,13 nickel metallaphotoredox catalysis has received wide attention over the past few years. Owing to its ability to undergo facile oxidative addition with both alkyl and aryl electrophiles combined with its low tendency for β-hydride elimination, nickel is often the metal of choice for alkyl coupling reactions.3,14 Indeed, nowadays aryl halides can be routinely coupled with C-centered radicals generated from a wide variety of radical precursors, e.g. carboxylic acids,15,16 aldehydes,17 sulfinates,18 alkyl bromides,19 oxalates,20 trifluoroborates,21,22 or silicates.23,24 Hence, metallaphotoredox catalysis has rapidly matured into a reliable catalysis platform for the facile assembly of structurally complex molecules that are of potential interest to drug discovery programs. Although numerous other transformations have been rendered DNA-compatible over the past few years,25−29 metallaphotoredox catalysis would be another valuable asset © XXXX American Chemical Society
to DNA-encoded chemistries. The combination of split-andpool synthesis with unique, covalently linked DNA tags30 has proven truly transformative for the pharmaceutical industry and enabled the synthesis and screening of potential drug leads on an unprecedented scale.31−37 The resulting DNA-encoded libraries (DELs) typically consist of 106 to 1012 druglike molecules38,39 which can be screened against biological targets in a single experiment.40,41 More specifically, an immobilized protein of interest is incubated with DELs, and afterward nonbinding library members are removed by washing steps (affinity selection). Remaining high affinity binders42,43 are then released, and the incorporated DNA bar codes are amplified and decoded. This is made possible through the extraordinary sensitivity of the polymerase chain reaction (PCR) in conjunction with the prowess of subsequent highthroughput DNA sequencing.44 Importantly, this technology is extremely material-saving as only attomole quantities of each library member and minute amounts of the biological target (∼0.3 nmol) are needed per screen.45,46 However, the required presence of a DNA label imposes some limitations with regards to the preparation of DELs. First Received: April 16, 2019 Revised: June 4, 2019 Published: June 21, 2019 A
DOI: 10.1021/acscombsci.9b00076 ACS Comb. Sci. XXXX, XXX, XXX−XXX
Research Article
ACS Combinatorial Science and foremost, the reaction conditions and all reagents must be DNA-compatible; that is, they must not degrade or modify the DNA identification tag.47 Thus, harsh reaction conditions (e.g., acidic pH or reaction temperature >100 °C) and highly reactive reagents have to be omitted. Furthermore, all transformations must typically be carried out in aqueous solution as the solubility of DNA is very limited in organic solvents. However, this latter property can also be exploited for facile, yet efficient, purification of DNA-tagged intermediates via ethanol-induced precipitation. It is noteworthy that recent reports also demonstrated chemical transformations under largely anhydrous conditions by sequestering the DNA on a quaternary ammonium ion-based solid support.73,74 Lastly, DNA-encoded chemistry typically needs to proceed at high dilution of the DNA substrate (
